Humans are remarkable hosts to microbes, and we have in fact co-evolved as highly plethoric communities. Human-associated microorganisms (the microbiome) are present in numbers exceeding the quantities of human cells by at least 10-fold beginning in the neonatal period The collective genome (the metagenome) exceeds our human genome in terms of gene content by more than 150-fold. With respect to microbiota and preterm birth, it has generally assumed that the majority of intrauterine infections originate in the lower genital tract, with microbiota ascending into the otherwise sterile intrauterine environment to infect the placenta (preterm birth), fetal membranes (chorioamnionitis), umbilical cord (funisitis), and the fetus (sepsis). However, we and others have recently demonstrated that (1) the vaginal and gut microbiome communities are distinctly structured in pregnancy, and (2) the placenta is in fact not sterile, but rather harbors a low-abundance microbiome which is likely acquired through hematogenous transmission of the oral microbiome. Based on our prior studies and preliminary data, our central hypothesis is that a distinct and largely commensal resident microbiome in pregnancy renders risk for preterm birth. In order to prove this hypothesis, we will execute three essential aims: Aim 1 will use 16S-based approaches with inferred metagenomics employing samples from at-risk gravidae enrolled at <20 weeks gestation to reveal distinct microbial communities which occur in association with preterm birth; Aims 2&3 will use whole-genome shotgun sequencing with integrated host genomics, metatranscriptomics, and metabolomics to build on our functional computational pipelines and enable species identification, microbial gene catalogues, metabolic reconstructions, and mechanisms and networks of susceptibility to preterm birth. In addition, we describe our concomitant efforts to build a community resource for future large-scale studies on host and microbe biomarkers acquired in this set of preterm, near term, and term births. By utilizing our state-of-the-science technology and analysis tools in a longitudinal case-cohort of preterm birth subjects, we will be able to transform discovery based metagenomics and multi'omics science into readily translatable mechanistic studies at a previously unparalleled level. Our proven abilit to execute such clinical studies and utilize high-throughput technologies makes such large-scale team science feasible. Because preterm birth is prevalent in both the developed and developing world, these studies are of broad significance to our population's disease burden and will lead to potential innovative interventions.